APPLICANT'S ABSTRACT: Smoking of cocaine base ("crack") has emerged as a significant substance abuse problem yet there have been comparatively few attempts to model the physiological or behavioral effects of inhaled cocaine base in animals. The major obstacle in attempting to study effects of cocaine base has been the lack of technologies available for the generation on demand of a defined and reproducible test atmosphere that will achieve alveolar deposition patterns in animals that model those in humans. A method has been developed in this laboratory which allows the generation of precise, known concentrations of condensation aerosols of cocaine base whose particle characteristics are such that they are likely to be deposited in the lungs of laboratory animals. Additionally, we have shown that a pyrolysis product of cocaine base, methylecgonidine (MEG; anhydroecgonine methyl ester) base, is produced in model crack pipes and by other methods used to deliver cocaine base to animals or humans and that MEG base has effects on cardiovascular and pulmonary function. In the next three years of this project, we shall use the generator system to investigate the effects of cocaine base, MEG base and cocaine/MEG base mixtures in non-human primates (Squirrel monkeys; Saimiri sciureus) breathing atmospheres containing these compounds. These studies will not only provide empirical data on the effects of cocaine base inhalation but will also address whether MEG, in amounts likely to be encountered by the crack smoker, contributes to the physiological or behavioral sequelae of crack use. This project will: i. Describe concentration-related effects and duration-related effects induced by exposure to atmospheres containing cocaine base, MEG base and cocaine/MEG base aerosols on cardiovascular function (heart rate, blood pressure), pulmonary function (specific airway conductance) and temperature (rectal, skin) in squirrel monkeys; ii. Investigate whether acute tolerance phenomena are observed on repeated (within-session) exposure to these atmospheres, using the same cardiovascular, pulmonary and temperature end-points as above; lli. Examine the pharmacological mechanisms underlying the cardiovascular, pulmonary and temperature effects of breathing cocaine base and cocaine/MEG base in squirrel monkeys, investigating how different pharmacological agents may differentially affect cardiovascular and pulmonary responses; iv. Train squirrel monkeys to self-administer atmospheres containing aerosols of cocaine base using schedules that have previously been shown to maintain IV cocaine self-administration; describe concentration- and duration-related effects of cocaine base on self-administration; determine whether MEG base is self-administered and whether it alters the self-administration of cocaine base in squirrel monkeys; v. Using in vitro techniques, investigate the mechanism(s) which may underlie the transduction of the effects of MEG in vivo. These studies will have bearing on possible treatment strategies for cardiovascular, pulmonary and/or behavioral consequences of crack smoking in humans.